雷芬那辛的合成工艺优化

Improved Synthetic Process of Revefenacin

本研究对雷芬那辛(1)的合成工艺进行改进与优化。以异氰酸2-联苯酯(2)、N-甲基-N-羟乙基苄胺(5)和对氯甲基苯甲酸(7)为起始原料,依次经氯代和亲核取代反应,分别得到哌啶-4-基[1,1'-联苯]-2-基氨基甲酸酯(4)、N-(2-氯乙基)-N-甲基苄胺盐酸盐(6)和4-[(4-氨甲酰基哌啶-1-基)甲基]苯甲酸(9)。再通过2步汇聚式路线,4和6先进行亲核取代反应,再脱苄基得到1-[2-(甲胺基)乙基]哌啶-4-基[1,1'-联苯]-2-基氨基甲酸酯(10),最后,10与9反应得目标产物1。该工艺总收率60.6%(以2计),纯度99.9%。改进后的工艺生产成本降低,收率提高,同时避免产生多种杂质,所得中间体和产品纯度高、易提纯,已经过公斤级放大验证。

An improved synthetic process of revefenacin(1)was developed.Using 2-biphenyl isocyanate(2),N-methyl-N-hydroxyethyl benzylamine(5)and p-chloromethyl benzoic acid(7)as starting materials,through a series of reactions,piperidiu-4-yl[1,1'-biphenyl]-2-ylcarbamate(4),N-(2-chloroethyl)-N-methylbenzylamine hydrochloride(6)and 4-[(4-carbamoylpiperidiu-1-yl)methyl]benzoic acid(9)were obtained,respectively.Then through a two-step convergent strategy,4 and 6 undergo nucleophilic substitution reaction,and then debenzylated to obtain 1-[2-(methylamino)ethyl]piperidin-4-yl[1,1'-biphenyl]-2-yl carbamate(10),10 and 9 then were subjected to amide condensation to obtain the target compound 1 with a purity of 99.9%.The total yield of the process was 60.6%(based on 2).The optimized process reduced the production cost and significantly increased the yield,which had been verified by kilogram scale-up.Meanwhile,the generation of various impurities was avoided and the intermediates as well as products were obtained in high purity.